No Advantage for Endovascular Stroke Treatment Over IV tPA

Honolulu, Hawaii — A new trial shows outcomes with endovascular revascularization are not superior to those achieved with intravenous (IV) thrombolysis in the treatment of acute ischemic stroke.

The SYNTHESIS Expansion trial directly compared the strategies and found that at 3 months, there was no difference between the groups on the primary endpoint of survival free of disability.

"This trial did not show that endovascular therapy achieves superior outcomes as compared with intravenous thrombolysis, and our findings do not provide support for the use of the more invasive and expensive endovascular therapy over intravenous treatment," the researchers, with lead author Alfonso Ciccone, MD, from the Stroke Unit and Department of Neurology at Niguarda Ca' Granda Hospital, Milan, and Carlo Poma Hospital Mantua, Italy, conclude.

"At this point we have to conclude that IV tPA [tissue plasminogen activator] should remain the first-line treatment," Dr. Ciccone told Medscape Medical News. "It's disappointing for us [who] began the trial as a believer in endovascular therapy, but in the end, we're very happy because the result is very robust."

Trial results were presented here at the International Stroke Conference (ISC) 2013 and published online simultaneously February 6 in the New England Journal of Medicine.

SYNTHESIS Expansion

Intravenous tPA is the standard treatment for stroke, but more than half of patients still die or recover incompletely, the authors write. Endovascular approaches have been used for many years, they note, and result in a higher rate of recanalization of the affected cerebral artery, estimated at more than 80%, than with intravenous therapy (46%).

Still, these approaches haven't yet been directly compared, they write. "Recanalization is not invariably associated with a favorable clinical outcome, and it is not known whether clinical outcomes are superior with endovascular therapy" vs IV tPA.

For this trial, the researchers randomly assigned 362 patients with acute ischemic stroke within 4.5 hours of symptom onset to receive IV tPA or endovascular therapy, including intraarterial thrombolysis with tPA, mechanical clot disruption or retrieval, or a combination of these interventions.

"This was a very pragmatic trial," Dr. Ciccone said, "comparing the best endovascular treatment with the best medical therapy, and the best can change depending on the patient's situation. It was not driven by industry, since industry is usually interested in 1 device." Instead, it was sponsored by the Italian Medicines Agency.

Patients were to be treated as soon as possible after randomization; in the end, the median time from symptom onset to start of treatment was 3.75 hours for those undergoing endovascular therapy and 2.75 hours for IV tPA, a significant difference of 1 hour (P < .001).

The primary outcome was survival free of disability, defined as a score of 0 or 1 on the modified Rankin scale at 3 months.

Final results of the trial showed that the proportion of patients who survived free of disability by this measure was not statistically different between groups, although the endpoint was actually numerically higher with IV tPA.

Table. SYNTHESIS Expansion: Primary Endpoint

Outcome	Endovascular Therapy	IV tPA	Adjusted Odds Ratio (95% Confidence Interval)	P Value
Survival free of disability at 3 months, n (%)	55 (30.4)	63 (34.8)	0.71 (0.44 - 1.14)	.16

Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6 patients in both groups, Dr. Ciccone and colleagues note. There was no difference between groups in rates of other serious adverse events, or in the case fatality rate.

Although the time to treatment achieved in this trial is remarkably fast for endovascular therapy, it still means the vessel is closed for an additional hour, and whether this may have made some difference in terms of outcomes is not clear, he said. The researchers did adjust for stroke severity — because severe strokes tend to present faster than less severe strokes — but no effect was evident on that analysis to suggest any benefit.

During his presentation here, Dr. Ciccone was challenged by attendees on several issues. Anthony Furlan, MD, from Case Western Reserve University, Cleveland, Ohio, for example, pointed out that no information was available on sites of occlusion between the treatment groups or rates of recanalization. He pointed out that the investigators were not able to distinguish how many patients had extracranial internal carotid occlusion in the 2 groups, which Dr. Ciccone acknowledged was true. "I think that's a key variable that would make me hesitate to draw too firm a conclusion."

Another attendee interpreted the findings differently. He suggested that although the time to treatment in the endovascular group was 1 hour longer than in the IV tPA group, the similar outcomes in the treatment groups suggest, conversely, that endovascular therapy actually extends the therapeutic time window by 1 hour. He also pointed out that clots were found in only 165 of the 181 patients in the endovascular group, and "in those patients it's really not meaningful to consider endovascular treatment."

In the paper, Dr. Ciccone and colleagues acknowledge that device technology is "evolving rapidly" and note that "it is conceivable that the latest-generation devices, called stentrievers, which were used infrequently in this trial, could provide greater benefit if used widely."

"Physicians' belief that interventional approaches were superior to medical treatment was a serious obstacle in organizing randomized trials in the past decade," the authors point out. "The high rate of recanalization with endovascular treatment might give the impression that this method is effective in most cases, although it may provide no clinical benefit in almost half the patients."

Physicians' Belief

The issue of perceived equipoise was also an issue for another trial being presented in full here, the long-anticipated Interventional Management of Stroke III (IMS III) trial. IMS III was a phase 3, randomized, open-label trial comparing a combined intravenous and intraarterial approach to stroke treatment to intravenous tPA alone.

As reported previously by Medscape Medical News, the trial was halted in April 2012 when a preplanned interim analysis showed "a low likelihood of demonstrating the pre-specified clinically significant difference in benefit between treatment arms of the study," according to a statement from the National Institute of Neurological Disorders and Stroke, which funded the trial at that time.

The Data and Safety Monitoring Board's decision was based on the primary outcome of the trial, the modified Rankin score at 3 months, "meeting the threshold for futility," the statement added. "While enrollment was stopped because of futility, no serious safety concerns were identified."

Full results will be presented here by principal investigator Joseph P. Broderick, MD, from the University of Cincinnati, Ohio, on Thursday, February 7, at a session dedicated just to this trial.

Dr. Joseph P. Broderick

Asked for some perspective on the SYNTHESIS Expansion results, Dr. Broderick told Medscape Medical News that the researchers did well to have only 1 hour between the groups in terms of time to treatment, calling it "one of the biggest accomplishments" of the trial.

But there's really no signal [of benefit] at all," he said. "It's just about as negative a trial as you could get. If anything, it tends to favor tPA."

Like Dr. Furlan, Dr. Broderick also commented on the lack of data on recanalization rates for the various clot locations. "That's one of the things I would have liked to have seen."

For the Routine Patient, tPA

Asked for comment, Larry Goldstein, MD, professor of neurology at Duke University Medical Center and director of the Duke Stroke Center, Durham, North Carolina, said the study was well designed and properly powered.

"What they found was no difference, and if anything a slight trend favoring IV tPA, which I think comes as somewhat of a surprise to some, because the recanalization rates are better with direct visualization of the clot, but that comes at a risk of time, because it takes longer to activate all the things you need to do to treat intraarterially."

He pointed out that in this trial, the researchers didn't have to demonstrate a clot before beginning endovascular therapy, "and that right now, clinically, would be the way most places would approach it; that you might get an MR [magnetic resonance] angiogram or CT [computed tomography] angiogram up front, emergently, to see whether you could identify an occluded vessel that could be responsible for the patient's stroke, that might be reachable before sending them through for a catheter-based study."

The question then is who, if anyone, should be considered for endovascular therapy at this point. "One point is that there are groups of patients who can't be treated with intravenous tPA, for example patients who have had recent surgery. There are a variety of other exclusions that would not necessarily exclude someone from endovascular therapy," Dr. Goldstein added. "So what this suggests is that this approach might be very reasonable in those patients, since there was no big difference between the 2 groups."

For the routine patient, however, he concluded, "regardless it seems of whether you can detect a clot or not, intravenous tPA seems from this study to be more reasonable given all the costs and other potential complications that can happen, and did happen in some patients with endovascular therapy."

The trial was funded by the Italian Medicines Agency; there was no industry support. Dr. Goldstein has disclosed no relevant financial relationships.

N Engl J Med. Published online February 6, 2013. Abstract

International Stroke Conference (ISC) 2013. Abstract 60. Presented February 6, 2013.